The immune-hematopoietic-neural axis encompasses the neuroendocrine system. These two systems cooperate via biochemical cross-talk. A particular cytokine or neuropeptide can be produced in cells of both neural and peripheral tissue, the latter including lymphoid organs and bone marrow, among others. Soluble factors mediate this bidirectional communication between the nervous and immune/hematopoietic systems. Due to this crosswalk, changes in one system often influence functional changes in the other. In fact, studies show that the onset of hematopoiesis is correlated with complete innervation of the bone matter.
Stress, either physical, chemical or psychological, induces soluble brain derived factors and has been implicated in altered immune functions. Stress has also been associated with the incidence, relapse and prognosis of cancer. Specifically, stress-induced neurohormones have been implicated in the development of breast cancer. Biological homeostasis is achieved by the complex interacting network of all these soluble factors. The interactions of neurohormones and neurotransmitters are not mutually exclusive of the interactions exerted by cytokines and neurotrophic factors. Dysregulated and inappropriate expression of factors, such as neuroendocrine-derived peptides, disrupts homeostasis. Ultimately, tumors may develop as a result of disrupted homeostasis. An example of this type of dysregulation is the constitutive expression of neurokinins observed in some tumors.
The Preprotachykinin-I (PPT-I) gene encodes a family of peptides that interact with a network of soluble factors in neural and non-neural tissues to exert biological pleiotropism, such as neurotransmission, immune modulation and hematopoiesis (Rameshwar, P. 1997, Clin. Immunol. Immunopath, 85:129; Maggi, C. A. 1996, Pharmacol. Res. 33:161; Merril, J. E. et al. 1995, FASEB J., 9:611). The role of PPT-I in hematopoiesis and angiogenesis, and its over expression in breast and other cancers that metastasize to the bone marrow, suggests that PPT-I has a central role in: bone marrow metastasis (Singh, D. et al. 2000, Proc. Nat'l. Acad. Sci U.S.A. 97:388; Hennig, I. M. et al. 1995, Int. J. Cancer 61:786; Jones, D. A. et al. 1997, Peptides 18:1073). The evolutionarily conserved sequence of PPT-I peptides underscores the importance of the pleiotropism that these peptides demonstrate in interactive biological functions (Moore, T. C. et al. 1990 Immunopharmacol 20:207). The ability to manipulate and understand the regulation of PPT-I may help to facilitate modulation of the molecular mechanisms mediated by this gene that underlie organ specific functions and provide new insights into human pathology such as tumorgenesis, hematological diseases, nerve damage and other brain-associated functions and/or behavior.
Neurokinins are a family of neurotransmitters derived from expression of the preprotachykinin-I (PPT-I) gene. This gene is also expressed in a variety of non-neuronal cells. The PPTI gene is alternatively spliced into one of four transcripts, α, β, γ, and δ PPT-I. Each transcript can produce substance P (SP). The γ and δ PPT-I transcripts produce neurokinin-A (NK-A). Various N-terminally extended forms of NK- are also expressed from the PPT-I gene.
Regulated expression of SP and NKA and other biological mediators act in concert to maintain homeostasis. Overproduction of SP and NKA can contribute to neoangiogenesis, facilitating the growth of metastatic tumors. While SP exerts angiogenic properties directly, NK-A has the potential to exert indirect angiogenic function through TGF-β production. The elucidation of this relationship is desirable for developing therapeutic agents for the treatment of cancer. In particular, agents which regulate the expression of PPT-I may be efficacious in the treatment of cancers and other hematopoietic disorders.
In the bone marrow, the two major PPT-I peptides, through their natural neurokinin receptors, NK-1 and NK-2, exert opposing influences, inhibitory and stimulatory, on hematopoiesis at the level of the mature and immature progenitors (Rameshwar, P. et al. 1997, Leuk. Lymphoma 28:1). Therefore, hematopoietic stimulation by one of the major PPT-I peptides may be clinically important in hematologic deficiencies such as in the development of neutropenia and also other inflammatory responses (Cao, T. et al. 2000, J. Immunol 164:5424). The inhibitory effect could be important in protection of the lymphohematopoietic stem cells in the bone marrow, where maintaining cell quiescence is often important. Furthermore, PPT-I is involved in the cellular and molecular connection among the immune, neuroendocrine and hematopoietic systems (Rameshwar, P. 1997, supra.). Thus, the regulation of PPT-I has relevance to bone marrow-associated biology, including the rapidly evolving fields of transplantation and gene therapy and also, inflammatory processes.
Bone marrow fibrosis is a pathological secondary reaction which occurs in certain myeloproliferative disorders. Whereas the mechanisms that lead to bone marrow fibrosis are poorly understood, it has been hypothesized that soluble factors such as platelet derived growth factor (PDGF), transforming growth factor β (TGF-β) and epidermal growth factor (EGF) act to induce deposits of extracellular matrix proteins in the bone marrow. TGFβ stimulates synthesis of collagen and fibronectin in fibroblasts and also augments the proliferation of human bone marrow fibroblasts by EGF and PDGF. The NK-1 receptor shares homology with regions of fibronectin. Preliminary studies show that substance P (SP), the preferred ligand for NK-1, binds to fibronectin in the sera of patients with various categories of bone marrow fibrosis. SP is a fibrogenic factor and a stimulator of macrophages. As fibroblasts and macrophages are implicated in the pathophysiology of bone marrow fibrosis, SP is transported to the bone marrow and other organs via binding to fibronectin. Accordingly, PPT-I (the gene from which SP is derived) provides a suitable target for treatment of patients with bone marrow fibrosis. Since bone marrow fibrosis is secondary to myeloproliferative disorders, PPT-I genes, their encoded peptides and their receptors, and/or pathways associated with the products of these genes can also serve as targets to identify beneficial therapeutic reagents for treating patients with such disorders.